It is well known that the energy coinage of the cell is adenosine triphosphate (ATP). During anabolism, the energy derived from the metabolism of nutrients is transferred to high energy phosphate bonds of ATP. The energy in these bonds is expended during the energy consumption phase. An important and "costly" expenditure, in which ATP is rapidly cycled, is that required for muscular contraction.
The energy buildup steps occur within the muscle cell during two basic processes. Oxidative phosphorylation replenishes ATP by the breakdown of circulating fatty acids, glucose and intramuscular glycogen and triglycerides. Anaerobic phosphorylation provides ATP from creatine phosphate, circulating glucose and intramuscular glycogen via kinase reactions such as the myokinase reaction. U.S. Pat. No. 5,714,515 describes the administration of compositions containing pyruvate, an intermediate breakdown product of glucose, to enhance recovery from surgical or accidental trauma, shock, exhaustion due to prolonged physical effort and other indications. U.S. Pat. No. 5,709,971 discloses the administration of other glucose metabolites, namely glyceraldehyde-3-phosphate, phosphoenolpyruvate and 3-phosphoglycerate, in combination with nicotineadeninedinucleotide, coenzyme A and acetyl coenzyme A.
A different approach to increasing the substrates available for production of ATP that has been employed is the administration of the amino acid L-carnitine, which is thought to enhance the transport and absorption of fatty acids into mitochondria, the site of oxidativc phosphorylation. U.S. Pat. No. 4,968,719 describes the use of L-carnitine for the treatment of peripheral vascular diseases.
Regardless of whether the high energy phosphate bonds of ATP are generated oxidatively or anaerobically, and irrespective of the substrates used for its generation, ATP cannot be synthesized unless the precursors of the ATP molecule itself are available. The resynthesis of the ATP molecule can occur by de novo or salvage pathways.
In the synthesis of ATP via the nucleotide salvage pathway, the nucleotide precursors that may be present in the tissue are converted to AMP and further phosphorylated to ATP. Adenosine is directly phosphorylated to AMP, while xanthine and inosine are first ribosylated by 5-phosphoribosyl-1-pyrophosphate (PRPP) and then converted to AMP. Ribose is found in the normal diet only in very low amounts, and is synthesized within the body by the pentose phosphate pathway. In the de novo synthetic pathway, ribose is phosphorylated to PRPP, and condensed with adenine to form the intermediate adenosine monophosphate (AMP.) AMP is further phosphorylated via high energy bonds to form adenosine diphosphate (ADP) and ATP.
Synthesis by the de novo pathway is slow. Normally, AMP synthesis is believed to occur mainly by the salvage pathway, however, following anoxia or ischemia, the activity of the de novo pathway is increased.
During energy consumption, ATP loses one high energy bond to form ADP, which can be hydrolyzed to AMP. AMP and its metabolites adenine, hypoxanthine and inosine are freely diffusible from the muscle cell and may not be available for resynthesis to ATP via the salvage pathway.
In U.S. Pat. No. 4,719,201, it is disclosed that when ATP is hydrolyzed to AMP in cardiac muscle during ischemia, the AMP is further metabolized to adenosine, inosine and hypoxanthine, which are lost from the cell upon reperfusion. In the absence of AMP, rephosphorylation to ADP and ATP cannot take place. Since the precursors were washed from the cell, the nucleotide salvage pathway is not available to replenish ATP levels. It is disclosed that when ribose is administered via intravenous perfusion into a heart recovering from ischemia, recovery of ATP levels is enhanced.
Pliml, in German Patent No. 4,228,215, found that oral ribose was effective in treating cardiac insufficiency and hypovolemic shock in humans.
The advantage of the administration of pentoses such as ribose or xylitol to prevent pain and stiffness of skeletal muscle in patients suffering from the autosomal recessive genetic disease myoadenylate deaminase (MAD) deficiency was shown by Zollner et al. (Klinische Wochenshritt 64:1281-1290, 1986.) This disease is characterized by permanent muscular hypotonia, excessive muscular weakness, fatigue, soreness, burning pain, stiffness and cramps. These symptoms are considered to be consequences of the interruption of the ATP cycle. Dephosphorylation of ATP is inhibited by the accumulation of AMP, resulting in less available energy to effect muscle contraction and relaxation. However, even though symptoms of MAD-deficient patients were relieved by administration of ribose, the intracellular levels of adenine nucleotides remained abnormally high and normal volunteers experienced no beneficial effect from ribose administration. (Gross, Reiter and Zollner, Klinische Wochenshritt, 67:1205-1213, 1989.)
Tullson et al. (Am. J. Physiol., 261 (Cell Physiol. 30) C343-347, 1991) cite references showing that high intensity exercise increases degradation and subsequent loss of AMP from isolated muscle. They further disclose that adding ribose to the perfusate in a rat hindquarter preparation increases the de novo synthesis of AMP in sedentary muscle, but does not eliminate the decline in de novo synthesis seen in contracting muscle. Carniglia, et al, U.S. Pat. No. 4,871,718, disclose that when a complex mixture comprising amino acids, metabolites, electrolytes and ribose or a precursor of ribose, was administered orally as a dietary supplement to race horses, increases in intracellular ATP levels and physical performance result. The performance evaluation was anecdotal, however, based on the subject's performance history.
Thus, a continuing need exists for simple methods to enhance skeletal muscle performance in normal mammals; that is, mammals that are not at the time of application of the method experiencing ischemia, prior to or undergoing physical activity. A need also exists for a method to increase the energy level of mammals to provide an increased feeling of well-being.